Response to neoadjuvant immune checkpoint inhibitor (ICI)-based therapy in oncogene-driven resectable non-small cell lung cancer (NSCLC).
Authors: Samuel Rosner, Lavanya Sivapalan, Marianna Zahurak, Rohit Thummalapalli, Roni Rayes, Sydney Connor, Khaled Sanber, Joshua E. Reuss, Gavin Pereira, Kellie Nicole Smith, Valsamo Anagnostou, Stephen Broderick, David Randolph Jones, Julie R. Brahmer, Kristen A. Marrone, Jonathan Spicer, Jamie E. Chaft, Patrick M. Forde
Journal: Journal of Clinical Oncology (2023)

8523 Background: Neoadjuvant (NEO) chemotherapy (chemo) plus nivolumab (nivo) has received FDA approval for treatment of resectable NSCLC, demonstrating superior event-free survival compared to chemo alone. However, outcomes of NEO ICI-based therapies in patients (pts) with oncogene-driven (OD)-NSCLC remains an unanswered question. Methods: We conducted a retrospective secondary analysis of pts enrolled in the clinical trial NCT02259621 with clinical stage I-IIIA NSCLC, treated with NEO ICI-based therapies: nivo alone, nivo+ipilimumab (ipi), or nivo+chemo followed by surgery. Pts underwent baseline genomic profiling using NGS. Pts with KRAS, EGFR, MET, BRAF, ALK, HER2, ROS1, RET or NTRK alterations were identified as OD-NSCLC. STK11 and KEAP1 mutations (muts) were also recorded. For pts who underwent definitive resection (DR) and baseline NGS testing, association of OD-status and clinical outcomes, including major pathologic response (MPR) and recurrence-free survival (RFS) are reported. Proportions are reported with exact 95% binomial confidence intervals (CI). Binomial probabilities are compared with Chi-square or Fisher’s exact tests. RFS and median follow-up (f/u) are reported using the Kaplan-Meier (KM) and reverse KM methods, respectively. Results: 61 pts received NEO ICI-based therapy: 60% treated with nivo alone, 15% with ipi+nvo and 25% with chemo+nivo. 92% of pts underwent DR. Pathologic complete response (pCR) and MPR rates were, 12.5% and 37.5%, respectively. Baseline NGS testing was available for 47 pts, of whom, 49% had OD-NSCLC, with the majority (78%) harboring a KRAS mut. Additional OD alterations included non-classical EGFR (9%), METex14 skipping (9%) and ROS1 fusion (4%), of whom, 3/5 pts had a MPR after NEO-ICI. STK11 muts were noted in 16% pts, and co-altered with KRAS in 9%. Median f/u for OD-NSCLC was 42.58 months. Pts with OD-NSCLC had comparable RFS after NEO-ICI compared to those with non-OD-NSCLC (HR 0.64, CI 0.19-2.13, p=0.5), including those with KRAS+ disease (HR 0.73, CI 0.2-2.73, p=0.6). Pts with co-mut KRAS+ STK11+ trended toward shorter RFS compared to KRAS+ STK11- (HR 6.36, CI 0.56-72.82, p=0.1). STK11+ also trended toward shorter RFS without reaching statistical significance (HR 2.51, CI 0.67-9.35, p=0.17). No significant associations between OD-status and MPR rates were seen, however KRAS+ (4/18) vs. Kras- (13/29) trended toward lower MPR rate (p=0.1). Four of 5 pts with disease progression preventing DR harbored an STK11 or KEAP1 mut. Conclusions: Findings from this cohort treated with various NEO ICI-based therapies, suggests comparable RFS, regardless of OD status- with the majority harboring KRAS muts. Lower MPR rates were observed for pts with KRAS+ tumors. STK11 mut and KRAS+ STK11+ co-mut status both trended toward shorter RFS, though definitive conclusions are limited by cohort size and treatment heterogeneity.